Sputum inflammatory, neural, and remodeling mediators in eosinophilic and noneosinophilic asthma.

BACKGROUND: Neural and remodeling mechanisms may play a role in asthma, particularly noneosinophilic asthma (NEA). OBJECTIVE: To assess sputum mediators associated with neural, remodeling, and inflammatory mechanisms in eosinophilic asthma (EA), NEA, and participants without asthma. METHODS: A total of 111 participants with and 62 without asthma (14-21 years old) underwent sputum induction, exhaled nitric oxide, atopy, and spirometry tests. There were 24 mediators measured in sputum using enzyme-linked immunosorbent assay or bead array. Eosinophilic asthma (n = 52) and NEA (n = 59) were defined using a sputum eosinophil level cut-point of greater than or equal to 2.5%. RESULTS: Elevated levels of nociceptin (median: 39.1 vs 22.4 ng/mL, P = .03), periostin (33.8 vs 9.4 ng/mL, P = .01), and ECP; (220.1 vs 83.7 ng/mL, P = .03) were found in patients with asthma compared with those without asthma. Nociceptin was elevated in EA (54.8 vs 22.4 ng/mL, P = .02) compared with participants without asthma. Eosinophilic asthma had higher levels of inflammatory mediators (ECP: 495.5 vs 100.3 ng/mL, P ≤ .01; interleukin-1ß: 285.3 vs 209.3 pg/mL, P = .03; histamine: 5805.0 vs 3172.5 pg/mL, P < .01) and remodeling mediators (VEGF-A); 3.3 vs 2.5 ng/mL, P = .03; periostin: 47.7 vs 22.1 ng/mL, P = .04) than NEA. Whereas macrophages were associated with neural mediators, for example, neurokinin A (r = 0.27, P = .01) and nociceptin (r = 0.30, P = .02), granulocytes were associated with inflammatory and remodeling mediators (eg, ECP and VEGF-A correlated with neutrophils (r = 0.53 and r = 0.33, respectively, P < .01) and eosinophils (r = 0.53 and r = 0.29 respectively, P ≤ .01). CONCLUSION: Elevated levels of nociceptin and inflammatory and remodeling markers were found in EA, but no evidence for neural and remodeling pathways was found in NEA. Neural and remodeling mechanisms seem to coexist with inflammation.

Heart rate variability as a marker of autonomic nervous system activity in young people with eosinophilic and non-eosinophilic asthma.

OBJECTIVE: An imbalance in autonomic nervous system (ANS) activity may play a role in asthma, but it is unclear whether this is associated with specific pathophysiology. This study assessed ANS activity by measuring heart rate variability (HRV) in eosinophilic (EA) and non-eosinophilic asthma (NEA) and people without asthma. METHODS: HRV, combined hypertonic saline challenge/sputum induction, exhaled nitric oxide (FeNO), skin prick tests to measure atopy, and spirometry tests were conducted in teenagers and young adults (14-21 years) with (n = 96) and without (n = 72) generally well-controlled asthma. HRV parameters associated with sympathetic and parasympathetic ANS branches were analyzed. EA and NEA were defined using a 2.5% sputum eosinophil cut-point. Airway hyperreactivity (AHR) was defined as ≥15% reduction in FEV1 following saline challenge. RESULTS: HRV parameters did not differ between asthmatics and non-asthmatics or EA and NEA. They were also not associated with markers of inflammation, lung function or atopy. However, increased absolute low frequency (LFµs2; representing increased sympathetic nervous system (SNS) activity) was found in asthmatics who used ß-agonist medication compared to those who did not (median: 1611, IQR 892-3036 vs 754, 565-1592; p < 0.05) and increased normalized low frequency (LF nu) was found in those with AHR compared to without AHR (64, 48-71 vs 53, 43-66; p < 0.05). CONCLUSION: ANS activity (as measured using HRV analysis) is not associated with pathophysiology or inflammatory phenotype in young asthmatics with generally well-controlled asthma. However, enhanced SNS activity can be detected in asthmatics with AHR or who use ß-agonist medication.

Synthesis of new binary trimethoxyphenylfuran pyrimidinones as proficient and sustainable corrosion inhibitors for carbon steel in acidic medium: experimental, surface morphology analysis, and theoretical studies.

In this study, synthesis and assessment of the corrosion inhibition of four new binary heterocyclic pyrimidinones on CS in 1.0 M hydrochloric acid solutions at various temperatures (30-50 °C) were investigated. The synthesized molecules were designed and synthesized through Suzuki coupling reaction, the products were identified as 5-((5-(3,4,5-trimethoxyphenyl)furan-2-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (HM-1221), 2-thioxo-5-((5-(3,4,5-trimethoxyphenyl)furan-2-yl)methylene)dihydropyrimidine-4,6(1H,5H)-dione (HM-1222), 1,3-diethyl-2-thioxo-5-((5-(3,4,5-trimethoxyphenyl)furan-2-yl)methylene)dihydropyrimidine-4,6(1H,5H)-dione (HM-1223) and 1,3-dimethyl-5-((5-(3,4,5-trimethoxyphenyl)furan-2-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (HM-1224). The experiments include weight loss measurements (WL), electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PDP). From the measurements, it can be shown that the inhibition efficiency (η) of these organic derivatives increases with increasing the doses of inhibitors. The highest η recorded from EIS technique were 89.3%, 90.0%, 92.9% and 89.7% at a concentration of 11 × 10-6 M and 298 K for HM-1221, HM-1222, HM-1223, and HM-1224, respectively. The adsorption of the considered derivatives fit to the Langmuir adsorption isotherm. Since the ΔGoads values were found to be between - 20.1 and - 26.1 kJ mol-1, the analyzed isotherm plots demonstrated that the adsorption process for these derivatives on CS surface is a mixed-type inhibitors. Scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), atomic force microscope (AFM) and Fourier- transform infrared spectroscopy (FTIR) were utilized to study the surface morphology, whereby, quantum chemical analysis can support the mechanism of inhibition. DFT data and experimental findings were found in consistent agreement.

A fruitful century for the scalable synthesis and reactions of biphenyl derivatives: applications and biological aspects.

This review provides recent developments in the current status and latest synthetic methodologies of biphenyl derivatives. Furthermore, this review investigates detailed discussions of several metalated chemical reactions related to biphenyl scaffolds such as Wurtz-Fittig, Ullmann, Bennett-Turner, Negishi, Kumada, Stille, Suzuki-Miyaura, Friedel-Crafts, cyanation, amination, and various electrophilic substitution reactions supported by their mechanistic pathways. Furthermore, the preconditions required for the existence of axial chirality in biaryl compounds are discussed. Furthermore, atropisomerism as a type of axial chirality in biphenyl molecules is discussed. Additionally, this review covers a wide range of biological and medicinal applications of the synthesized compounds involving patented approaches in the last decade corresponding to investigating the crucial role of the biphenyl structures in APIs.

Novel biphenylidene-thiopyrimidine derivatives as corrosion inhibitors for carbon-steel in oilfield produced water.

The inhibiting efficiency of three newly synthesized organic compounds:5-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methylene)-1,3-diethyl-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (HM-1228), 5-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-dione (HM-1227) and 5-((4'-(dimethylamino)-[1,1'-biphenyl]-4-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione (HM-1226) in oilfield produced water on the corrosion of carbon steel has been examined via electrochemical measurements; potentiodynamic polarization (PDP) and electrochemical impedance (EIS) techniques. The adsorption of these compounds on the surface of carbon steel followed Langmuir isotherm. In addition, the surface morphology of uninhibited and inhibited carbon steel was examined by Atomic Force Microscopy (AFM), observing surface improvement when carbon steel samples exposed to the inhibited corrosive solutions. The average surface roughness (Ra) in oilfield produced water solution in the presence of 0.5 mM of HM-1228 inhibitor was 138.28 nm compared to the uninhibited surface 571.62 nm. To explore the corrosion inhibition mechanism, quantum chemical calculations and Monte Carlo simulations were utilized. The HM-1228 inhibitor demonstrated the highest corrosion inhibition efficiency at 94.8% by PDP measurements. The higher corrosion inhibition of compound HM-1228 can be attributed to the presence of di-N-ethyl groups that enhance both electron donating ability and lipophilic properties.

Synthesis of inventive biphenyl and azabiphenyl derivatives as potential insecticidal agents against the cotton leafworm, Spodoptera littoralis.

The emergence of pest resistance of Spodoptera littoralis (order; Lepidoptera, family; Noctuidae) towards the large scale of different classes of insecticides necessitates the development of some new poly-functionalized biphenyl and azabiphenyl with highly anticipated insecticidal bioresponse. Four new biphenyl carboxamidines 4a-d and four aza-analogue picolinamidine derivatives 8a-d were designed and prepared via the treatment of their corresponding carbonitriles with lithium-bis trimethylsilylamide [LiN(TMS)2], followed by hydrolysis with hydrogen chloride. Furthermore, these compounds were elucidated by spectral data, and their toxicity and insecticidal activity were screened against Spodoptera littoralis. Whereby, toxicological and biochemical aspects of the inventively synthesized biphenyl and azabiphenyl derivatives against the cotton leafworm, Spodoptera littoralis were inspected. As regards the indomitable LC50 and LC90 values, biphenyl and aza-analogues 8d, 8a, 4b, and 8b, revealed the furthermost forceful toxic effects with LC50 values of 113.860, 146.265, 216.624, and 289.879 ppm, respectively. Whereby, their LC90 values are 1235.108, 1679.044, 2656.296, and 3381.256 ppm, respectively, and toxicity index being 22.31%, 17.36%, 11.72%, and 8.76%, respectively, comparing with the already recommended, methomyl insecticide, lannate 90% SP (LC50, 25.396 and LC90, 57.860 and toxicity index, 100%). Additionally, electrochemical parameters via DFT studies were carried out for demonstrating and elucidation of structure-activity relationship (SAR) according to highly motived compounds, descriptors, and the in vivo insecticidal activities.

Asthma inflammatory phenotypes on four continents: most asthma is non-eosinophilic.

BACKGROUND: Most studies assessing pathophysiological heterogeneity in asthma have been conducted in high-income countries (HICs), with little known about the prevalence and characteristics of different asthma inflammatory phenotypes in low-and middle-income countries (LMICs). This study assessed sputum inflammatory phenotypes in five centres, in Brazil, Ecuador, Uganda, New Zealand (NZ) and the United Kingdom (UK). METHODS: We conducted a cross-sectional study of 998 asthmatics and 356 non-asthmatics in 2016-20. All centres studied children and adolescents (age range 8-20 years), except the UK centre which involved 26-27 year-olds. Information was collected using questionnaires, clinical characterization, blood and induced sputum. RESULTS: Of 623 asthmatics with sputum results, 39% (243) were classified as eosinophilic or mixed granulocytic, i.e. eosinophilic asthma (EA). Adjusted for age and sex, with NZ as baseline, the UK showed similar odds of EA (odds ratio 1.04, 95% confidence interval 0.37-2.94) with lower odds in the LMICs: Brazil (0.73, 0.42-1.27), Ecuador (0.40, 0.24-0.66) and Uganda (0.62, 0.37-1.04). Despite the low prevalence of neutrophilic asthma in most centres, sputum neutrophilia was increased in asthmatics and non-asthmatics in Uganda. CONCLUSIONS: This is the first time that sputum induction has been used to compare asthma inflammatory phenotypes in HICs and LMICs. Most cases were non-eosinophilic, including in settings where corticosteroid use was low. A lower prevalence of EA was observed in the LMICs than in the HICs. This has major implications for asthma prevention and management, and suggests that novel prevention strategies and therapies specifically targeting non-eosinophilic asthma are required globally.

Enhanced airway sensory nerve reactivity in non-eosinophilic asthma.

BACKGROUND: Neural mechanisms may play an important role in non-eosinophilic asthma (NEA). This study compared airway sensory nerve reactivity, using capsaicin challenge, in eosinophilic asthma (EA) and NEA and non-asthmatics. METHODS: Thirty-eight asthmatics and 19 non-asthmatics (aged 14-21 years) underwent combined hypertonic saline challenge/sputum induction, fractional exhaled nitric oxide, atopy and spirometry tests, followed by capsaicin challenge. EA and NEA were defined using a sputum eosinophil cut-point of 2.5%. Airway hyperreactivity was defined as a ≥15% drop in FEV1 during saline challenge. Sensory nerve reactivity was defined as the lowest capsaicin concentration that evoked 5 (C5) coughs. RESULTS: Non-eosinophilic asthmatics (n=20) had heightened capsaicin sensitivity (lower C5) compared with non-asthmatics (n=19) (geometric mean C5: 58.3 µM, 95% CI 24.1 to 141.5 vs 193.6 µM, 82.2 to 456.0; p<0.05). NEA tended to also have greater capsaicin sensitivity than EA, with the difference in capsaicin sensitivity between NEA and EA being of similar magnitude (58.3 µM, 24.1 to 141.5 vs 191.0 µM, 70.9 to 514.0) to that observed between NEA and non-asthmatics; however, this did not reach statistical significance (p=0.07). FEV1 was significantly reduced from baseline following capsaicin inhalation in both asthmatics and non-asthmatics but no differences were found between subgroups. No associations with capsaicin sensitivity and atopy, sputum eosinophils, blood eosinophils, asthma control or treatment were observed. CONCLUSION: NEA, but not EA, showed enhanced capsaicin sensitivity compared with non-asthmatics. Sensory nerve reactivity may therefore play an important role in the pathophysiology of NEA.